JP2018516942A - Composition of pranlukast-containing solid preparation with improved bioavailability and method for producing the same - Google Patents

Abstract

The present invention relates to a pharmaceutical composition containing pranlukast and a method for producing the same. The present invention is characterized in that the elution rate and bioavailability of pranlukast are remarkably improved as compared with conventional pranlukast-containing products. [Selection] Figure 6

Description

  The present invention relates to a preparation containing pranlukast, which is a poorly soluble drug, and a method for producing the same. More specifically, without using special equipment and processes that relatively increase the production cost of the preparation, only the production equipment and production methods that are accepted in the pharmaceutical industry are used to improve not only the dissolution rate but also the bioavailability. Therefore, pranlukast solid preparation that can reduce the dose per person of pranlukast as much as possible compared with the marketed product, and reduce the side effects associated with patient compliance and high-dose administration of drugs. And a manufacturing method thereof.

  The present invention relates to a preparation containing pranlukast and a method for producing the same, and by incorporating a formulation technique different from existing commercial products to further improve the bioavailability of pranlukast, It is characterized by maximizing the dose per stroke.

  The chemical name is 4-oxo-8- [4- (4-phenylbutoxy) benzoylamino] -2- (tetrazol-5-yl) -4H-1-benzopyran hemihydrate (4-oxo-8- Pranlukast, which is [4- (4-phenylbutoxy) benzoylamino] -2- (tetrazol-5-yl) -4H-1-benzopyran hemihydrate, is a product of Ono Pharmaceutical Co., Ltd. of Japan. )), Which has a mechanism of action that selectively binds to and antagonizes the action of leukotriene receptors. It is a drug used as a therapeutic agent. As of June 2015, typical examples of pranlukast-containing oral solid preparations containing pranlukast for adults marketed in the Republic of Korea include ONON capsules (pranlukast 112.5 mg / capsule, 2 capsules at a time, TOA ST shares Company), Planar Capsules (Pranlukast 112.5 mg / capsule, 1 capsule taken at a time, SK Chemical Co., Ltd.) and Plakanon Tablets (Pranlukast 75 mg / tablet, 1 tablet taken at a time, ( Ryuhan Yoko Co., Ltd.).

  It has been found that the site of maximum absorption of pranlukast upon oral administration is the small intestine, a drug belonging to BCS (Biopharmaceuticals Classification System) class II, which has strong adhesion cohesion and very low solubility. (1.2 μg / ml) has a disadvantage that the bioavailability at the time of oral administration is lower than that of other drugs. However, in the case of Onon capsules, such a problem of pranlukast could not be improved at the formulation stage, and eventually, a method of increasing the content of pranlukast was adopted. Onon capsules have been calculated and reported to be significant for treatment of the target disease only after taking 225 mg of pranlukast at a dose per dose, based on adults. However, this is not economical because of the large volume of a single drug to be taken, which may reduce the patient's compliance and may cause side effects associated with high doses of the drug. .

  Various studies have been conducted so far to improve the above-mentioned drawbacks of onon capsules.

  Korean Patent Registration No. 10-0389606 relates to a spray-dried granule having improved adhesion and cohesiveness of pranlukast, a production method thereof, and a method for improving the adhesion and cohesion of pranlukast. In this patent, in order to improve adhesion and cohesiveness, a method is adopted in which a saccharide, a binder and a surfactant are dissolved in purified water, and pranlukast is suspended to produce a spray-dried granulated product. Yes.

  However, the spray-dried granulated product disclosed in Korean Patent Registration No. 10-0389606 was not able to improve the solubility of pranlukast, although the adhesion and aggregation properties of pranlukast were improved. And the elution rate is very low, so that there is still a limit that the bioavailability is still low.

  Korean Patent Registration No. 10-1333223 relates to a method for producing a nano solid dispersion of pranlukast that can improve the low solubility of pranlukast and increase the bioavailability. The pranlukast nanosolid dispersion in the patent has a structure in which pranlukast is present in a carrier composed of polyethylene glycol and poloxamer, and the drug is improved while maintaining a nano-level particle size stably. The bioavailability is shown.

  However, in order to manufacture the nano-solid dispersion described in Korean Patent Registration No. 10-1333223, it is necessary to go through a mixing process, a thermal melting process, and a solvent evaporation process. However, there is a drawback that a complicated manufacturing process needs to be performed. In addition, there is a possibility that the organic solvent may remain in the solid dispersion using methanol / dichloromethanol as a cosolvent, and there is also a problem of environmental pollution due to the use of the organic solvent.

  Korean Patent Registration No. 10-1446129 relates to a production method comprising pranlukast and polyvinylpyrrolidone or a mixture of polyvinylpyrrolidone and a vinyl acetate copolymer or a production method comprising a pH adjuster in the mixture. In this patent, the solubility and elution rate are improved through simple mixing of pranlukast and hydrophilic polymer, but the ratio of hydrophilic polymer to the main component is high, and actually in-vivo. There is not enough experimental data to provide any material to support whether the bioavailability has actually improved.

  Korean Patent Registration No. 10-1086254 relates to a pranlukast solid dispersion composition having improved solubility and bioavailability and a method for producing the same. In this patent, a pranlukast solid dispersion composition characterized in that a polyvinylpyrrolidone-vinyl acetate copolymer for pranlukast is melted by heat at a weight ratio of 0.2: 1 to 10: 1. Is included. Planar capsules currently on the market (Pranlukast 112.5 mg / capsule, 1 capsule taken at a time, manufactured by SK Chemical Co., Ltd.) are formulated into solid dispersions disclosed in the above patents It is.

  However, it can be said that the solid dispersion disclosed in the above patent has a bioavailability of pranlukast that is about twice as high as that of the existing control drug Onon capsule, but it is melted by heat ( Since it cannot be manufactured using manufacturing equipment generally used in the pharmaceutical industry using hot melt, there is a burden on equipment investment, and the manufacturing process is complicated. In addition, since it can be said that the change of drug to amorphous due to hot melt is a thermodynamically unstable state, it may return to a crystalline form which is a stable form within the effective period of the product. Along with this, there is a limit that the solubility and bioavailability of the drug are concerned.

  Korean Patent Registration No. 10-0981751 contains a pharmaceutical composition in the form of a tablet comprising pranlukast granules containing a drug coating layer coated on the granule core. The patent is characterized by coating a suspension of pranlukast, binder and surfactant onto the granule core to produce granules and tableting. Currently marketed placanone tablets (pranlukast 75 mg / tablet, 1 tablet at a time, manufactured by Ryuhan Yoko Co., Ltd.) is a formulation of the spray-dried granules disclosed in the patent.

  However, the spray-dried granules disclosed in the above patent require a suspension process in which pranlukast is vigorously suspended in a solvent, and there are various manufacturing process variables associated with the spray-drying process, resulting in complicated production. There is a risk of increasing the manufacturing cost associated with the process. Although this patent improved the bioavailability of pranlukast and reduced the dose of the administered drug by 1/3 times compared to the existing control drug, ONON capsule, The dose volume per strike is 75 mg, further improving the bioavailability, reducing the dose of the drug, improving the patient's compliance, and side effects associated with the high dose of the drug Reducing the problem remains a problem.

  In general, the higher the dose of the drug, the higher the frequency of side effects associated therewith. Therefore, in the case of a drug with a high dose per dose, the bioavailability is increased and the dose is reduced to cause side effects. Need to reduce the frequency. However, in spite of the many prior arts mentioned above, among the pranlukast-containing preparations currently marketed in the Republic of Korea, the drug with the lowest drug volume per adult is Prakanone Tablet (Pranlukast 75 mg The drug also improves the solubility and dissolution rate of pranlukast, increases the bioavailability, and doses of 75 mg or less as a single dose. Even if it is administered, development of a product that exhibits clinical efficacy equivalent to or better than that of existing commercially available drugs is required.

  The present invention provides a solid production method having improved dissolution rate by using production equipment and methods that are commonly used in the pharmaceutical industry for pranlukast, which is a poorly soluble drug, and is more effective than the products marketed in the Republic of Korea. The purpose of the present invention is to provide a method for increasing the bioavailability of a strike and providing a clinically equivalent or better medicinal effect even if a dose of 75 mg or less is administered as a single dose. To do.

  The present invention has solved the above problems using the following means.

  (1) A pharmaceutical composition comprising granules produced by a wet granulation method and a pharmaceutically acceptable carrier, wherein the wet granulation method uses an alcohol having 1 to 6 carbon atoms as a binding solution solvent. The granules are characterized by comprising pranlukast, surfactant, binder and diluent, the granules or pharmaceutically acceptable carrier is from crospovidone, sodium starch glycollate and croscarmellose sodium A composition comprising two or more disintegrants selected from the group consisting of:

  (2) The composition according to (1), wherein the diluent is at least one selected from the group consisting of lactose and microcrystalline cellulose.

  (3) In the above (1) or (2), the binder is at least one selected from the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone-vinylacetate copolymer and hydroxypropylmethylcellulose. The composition as described.

  (4) The surfactant is at least one selected from the group consisting of polyethylene glycol-15-hydroxystearate, polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene sorbitan fatty acid ester and sodium lauryl sulfate. The composition according to any one of (1) to (3) above,

  (5) The composition according to any one of (1) to (4), wherein the pranlukast is 70 mg or less.

  (6) The composition according to any one of (1) to (5), wherein the diluent is contained in an amount of 20 to 60% based on the weight of the entire composition.

  (7) The composition according to any one of (1) to (6), wherein the binder is contained in an amount of 2 to 10% based on the weight of the entire composition.

  (8) The composition according to any one of (1) to (7), wherein the surfactant is contained in an amount of 5 to 20% based on the weight of the entire composition.

  (9) A preparation comprising the pharmaceutical composition according to any one of (1) to (8), wherein the preparation is a granule, a tablet, an oral disintegrant, a chewable tablet, a suspension A preparation characterized by being a tablet, capsule, fine granule or dry syrup.

  According to the present invention, the elution rate of pranlukast is improved, and the bioavailability is greatly improved as compared to the existing commercially available onon capsules. It exhibits clinical efficacy equivalent to or better than capsules (pranlukast 112.5 mg / capsule, 2 capsules per dose, manufactured by Toa ST Co., Ltd.).

The elution test result of Example 11, Example 14, Example 16, and an ONON capsule in the eluate of pH 6.8 is shown.

The elution test result of Example 12-Example 15 in the eluate of pH 4.0 + 2% PSB 80 (polysorbate 80) is shown.

The elution test result of Example 14, Example 17 and onon capsule in the eluate of pH 4.0 + 2% PSB 80 (polysorbate 80) is shown.

The pharmacokinetics test result in a tablet (Example 12) and onon capsule containing the granule manufactured with the manufacturing method which concerns on this invention in a human is shown.

The pharmacokinetics test result in the human of the tablet (Example 14) containing the granule manufactured with the manufacturing method which concerns on this invention, and an ONON capsule is shown.

The pharmacokinetics test result in the human of the tablet (Example 17) containing the granule manufactured with the manufacturing method which concerns on this invention, and an ONON capsule is shown.

  When a drug is formulated, granules may be produced as a pretreatment to ensure the fluidity of the powder, increase the density of the raw material, and improve the powder compressibility during tableting.

  Examples of the granule production method include a wet method and a dry method, and the present invention is characterized by utilizing a wet method. Specifically, the granule according to the present invention is mixed with pranlukast and a diluent in a high speed mixer used in the pharmaceutical industry, and the binder and the surfactant are suspended in an alcohol solvent. After making it turbid, it is kneaded with the binding solution and dried.

  Surprisingly, the inventor of the present invention is a commercially available product system in which the elution rate and the bioavailability are improved if the pranlukast granule is produced by a wet method using a high speed rotary mixer (HighSpeedMixer). It has been found that there are the following advantages compared to the hot melt method and the spray drying method.

  Manufacturing method of a planetary capsule (pranlukast 112.5 mg / capsule, 1 capsule taken at a time, manufactured by SK Chemical Co., Ltd.) formulated with a solid dispersion disclosed in Korean Patent Registration No. 10-108254 Melts the pranlukast and the polymer with heat in a state heated to 150 to 200 ° C. using a Melt-Flow-Indexer. However, the melt-flow indexer used for the production of the solid dispersion is not a device generally used in the pharmaceutical industry, and thus has a drawback that the manufacturing cost increases due to the investment of the device. In addition, since it melts with the heat | fever of 150-200 degreeC, when a main component and an excipient | filler are unstable to a heat | fever, it cannot apply. In particular, the final dosage form is a capsule dosage form, which is weaker in temperature and humidity than a tablet, and the capsule base may adversely affect drug dissolution and in vivo release.

  The manufacturing method of plakanone tablet (pranlukast 75mg / tablet, 1 tablet at a time, manufactured by Ryuhan Yoko Co., Ltd.) formulated with spray-dried granules disclosed in Korean Patent Registration No. 10-0981751 A granule is produced by coating a suspension of pranlukast, a water-soluble polymer, and a surfactant on the granule core, and is then tableted.

  However, in the production process described above, a process of vigorously dispersing when suspended in a solvent due to low solubility of pranlukast, for example, a propeller-container mixer, a homogenizer, or an ultrasonic vibrator Since the process of dispersing by, for example, is essential, the manufacturing time is prolonged. In addition, since it is forced to perform a spray-drying process, there exists a fault that manufacturing cost becomes high and passes through a complicated manufacturing process.

  However, in the case of the production process according to the present invention, since it can be produced only by a high speed mixer that is commonly used in the pharmaceutical industry, no further equipment investment is required, and a simple production process is adopted. So there is no unreasonable application to the pharmaceutical industry. In addition, since there is no process of suspending pranlukast in a solvent, the process of dispersing this is unnecessary, and as a result, the manufacturing process time can be shortened.

  In the production of the granule according to the present invention, as the diluent, those that are applicable in the field of pharmacology can be used. For example, xylitol, mannitol, isomalt, sorbitol, maltitol, purified sucrose, lactose, inositol, erythritol, crystalline fructose, trehalose, ribitol, arabitol, galactitol, lactitol and maltotritol, microcrystalline cellulose, sodium carboxymethylcellulose, carboxy One or more selected from methylcellulose calcium, hydroxypropylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose, gelatinized starch, sucrose, pregelatinized starch, starch, corn starch, hard silicic acid anhydride or crystalline cellulose can be used. However, in particular, microcrystalline cellulose, lactose, or a mixture thereof is preferable from the viewpoint of expression of the effect intended by the present invention. The diluent is preferably contained in an amount of 20 to 60% with respect to the weight of the entire pharmaceutical composition from the viewpoint of the manifestation of the effect intended by the present invention.

  In the production of the granule according to the present invention, a binder that is commonly used in the field of pharmacology can be used. For example, polyvinyl pyrrolidone, polyvinyl pyrrolidone-vinyl acetate copolymer, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyethylene glycol, polyvinyl alcohol, etc. can be selected and used. From the viewpoint of manifestation of the effect intended by the present invention, one or more selected from the group consisting of polyvinylpyrrolidone-vinylacetate copolymer and hydroxypropylmethylcellulose is preferable. Most preferred. The binder is preferably contained in an amount of 2 to 10% with respect to the weight of the whole pharmaceutical composition from the viewpoint of expression of the effect intended by the present invention.

  In the production of the granule according to the present invention, as the surfactant, polyethylene glycol-15-hydroxystearate (for example, Kolliphor (registered trademark) HS 15), polyoxyethylin glycolated natural or hydrogenated castor oil (for example, Kolliphor® RH 40), polyoxyethylene-polyoxypropylene copolymers (eg, poloxamers), polyoxyethylene sorbitan fatty acid esters (eg, polysorbates), sodium lauryl sulfate, glyceryl fatty acid esters (eg, glyceryl) Monostearate) can be used by selecting one or more thereof, and in particular, polyethylene glycol-15-hydroxystearate, polyoxyethylene-polyoxypropylene copolymer, polyoxye One or more selected from the group consisting of a tylene sorbitan fatty acid ester and sodium lauryl sulfate is preferable from the viewpoint of expression of the effect intended by the present invention. The surfactant is preferably contained in an amount of 5 to 20% with respect to the weight of the entire pharmaceutical composition from the viewpoint of expression of the effect intended by the present invention.

  In the production of the granule according to the present invention, it is preferable to use an alcohol having 1 to 6 carbon atoms as an alcohol solvent from the viewpoint of expression of the effect intended by the present invention. For example, lower alcohols such as methanol, ethanol, propanol, isopropanol, butanol may be used. In particular, when ethanol was used, the bioavailability of pranlukast was surprisingly improved.

  The pharmaceutical composition according to the present invention comprises the above-mentioned pranlukast solid granules and a pharmaceutically acceptable carrier.

  Examples of pharmaceutically acceptable carriers include excipients, disintegrating agents, lubricants and the like that are already known and used. Excipients that can be used in the present invention include xylitol, mannitol, isomalt, sorbitol, maltitol, purified sucrose, lactose, inositol, erythritol, crystalline fructose, trehalose, ribitol, arabitol, galactitol, lactitol and maltotritol, Microcrystalline cellulose, sodium carboxymethylcellulose, carboxymethylcellulose calcium, hydroxypropylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose, gelatinized starch, sucrose, pregelatinized starch, starch, corn starch, hard silicic acid or crystalline cellulose and these Contains disintegrants, and disintegrants include sodium starch glycolate, croscarmellose sodium, crospovidone And the like low-substituted hydroxypropyl cellulose, the lubricant, comprising sodium stearyl fumarate, magnesium stearate, stearic acid, colloidal silicon dioxide and the like.

  In particular, the absorption of pranlukast is mostly performed in the upper part of the small intestine, and the amount absorbed is gradually reduced as it progresses toward the lower part of the small intestine and the large intestine. Therefore, the present inventor does not need to reach the local absorption site until the disintegration of the pharmaceutical dosage form (tablet or capsule, etc.) is completed before reaching the upper part of the small intestine which is the maximum absorption site of the drug. Focusing on the fact that a large amount of drug is absorbed, an attempt was made to design a dosage form that quickly disintegrates before reaching the upper part of the small intestine. For this reason, when many repeated experiments were conducted, when two or more disintegrants selected from the group consisting of crospovidone, sodium starch glycolate and croscarmellose sodium were included, the intended effect of the present invention was obtained. I found that it was achievable. The disintegrant may be blended in granules or in a carrier that is not granules.

  The pharmaceutically acceptable carrier can be fluidly adjusted with respect to the total weight of the composition, and can be appropriately selected and used depending on the dosage form finally obtained. .

  Examples of the final dosage form of the pharmaceutical composition according to the present invention include various forms, such as granules, tablets, orally disintegrating agents, chewable tablets, suspension tablets, capsules, fine granules or dried. A syrup is preferable. These dosage forms can be produced by methods that are common in the pharmaceutical industry. For example, a tablet can be produced by mixing the granules disclosed in the patent with an excipient, a disintegrant, a lubricant and the like and compressing the mixture. A film coating step may be further performed for the purpose of improving drug stability, ease of taking, differentiation of properties, and the like.

  As can be seen from the following examples and test examples, the pharmaceutical dosage form according to the present invention improves the dissolution rate and bioavailability of pranlukast, and is an existing commercial control product, ONON capsule (Pranluca Even if the dose is about 4.5 times lower than the dose of 12.5 mg / capsule per dose, 2 capsules taken by Toa ST Co., Ltd. Indicates. Compared to existing products with improved bioavailability, the maximum dose per dose of Plakanone Tablets (Pranlukast 75 mg / tablet, 1 tablet at a time, manufactured by Ryuhan Yoko Co., Ltd.) Even if a lower dose is administered, the drug efficacy is equivalent or better. That is, even if the pharmaceutical composition according to the present invention contains pranlukast in an amount of about 70 mg or less, the pharmaceutical composition is clinically compared to existing pranlukast products at the time of single administration. The drug efficacy is equivalent or better. This meets the need for the development of products that are clinically equivalent to or better than existing over-the-counter drugs while reducing the frequency of side effects by administering small amounts of drugs that are required in the industry.

Hereinafter, an example is given and the present invention is explained. The following examples do not limit the present invention in any way.
[Mode for Carrying Out the Invention]

[Example]

[Examples 1 to 10] Production of pranlukast wet granules

  The main component (pranlukast) and the diluent were mixed in a high-speed rotary mixer (High Speed Mixer). A binder and a surfactant were dissolved in a solvent while stirring to obtain a binder solution. The binding solution was put into the above mixture and kneaded in a high-speed rotary mixer (High Speed Mixer). If necessary, a step of granulating with a filter medium was further performed, and the solvent was evaporated with a tray dryer. The dried product was sized with a filter medium to obtain pranlukast wet granules. The specific composition is shown in Table 1 below.

[Examples 11 to 17] Production of pranlukast-containing tablets

  Tablets were produced using the granules produced in Example 1, Example 6, Example 8, and Example 10 with the components and contents shown in Table 2 below. Specifically, the wet granulate and the disintegrant were mixed in a mixer, and then the lubricant was added and further mixed. Next, tableting and coating were performed to produce Examples 11-17. Examples 11-16 were prepared to contain 70 mg of pranlukast per tablet, and Example 17 was prepared to contain 50 mg of pranlukast per tablet.

[Test Example 1] Comparative dissolution test

  Korean medicine for 1 tablet and 2 onon capsules (pranlukast 112.5mg / capsule, 2 capsules taken by Toa ST Co., Ltd.) manufactured in Example 11, Example 14 and Example 16 Comparative dissolution was performed according to the second method of the standard dissolution test.

  The elution rate was measured while stirring at a rotation speed of 50 rpm in a state where 900 mL each of the pH 6.8 liquid was put into the eluent and maintained at 37 ± 0.5 ° C. Approximately 5 ml of eluate was taken at each time point, filtered through a 0.45 μm filter and analyzed by HPLC. The result is shown in FIG.

  As can be confirmed from FIG. 1, the dissolution rate of the tablet produced from the wet granule according to the present invention shows an aspect that is much higher than that of the onon capsule that is a commercial preparation.

[Test Example 2] Comparative dissolution test

  Elution of Korea's medicines against 1 tablet and 2 onon capsules (pranlukast 112.5 mg / capsule, 2 capsules each time, manufactured by Toa ST Co., Ltd.) produced in Examples 12 to 15 and Example 17 Comparative elution was performed according to the second test method. 900 ml of pH 4.0 solution containing 2% PSB 80 (polysorbate 80) was added to the eluent and kept at 37 ± 0.5 ° C., and the elution rate was measured while stirring at a rotation speed of 50 rpm. . Approximately 5 ml of eluate was taken at each time point, filtered through a 0.45 μm filter and analyzed by HPLC. The results are shown in FIGS.

  As can be confirmed from FIG. 2, the initial dissolution rate varies depending on the type of disintegrant and the input amount.

  As can be confirmed from FIG. 3, in the case of Example 17, the initial dissolution rate was higher than that of Example 14, and the dissolution rate as a whole was significantly higher than that of Onon capsule.

[Test Example 3] Evaluation of pharmacokinetics in humans

  In accordance with the present invention, the pharmacokinetics in humans was evaluated using the produced tablets (Example 12) and onone capsules (taken as 2 capsules) as a commercial preparation.

  Twelve healthy adults aged 20 to 40 years were divided into two groups (n = 6), and the tablets produced in Example 12 on an empty stomach (one tablet produced in Example 12 above, pranlukast 70 mg) (No. 1) Group 1) and a commercial formulation (2 capsules of the Onon capsule, total pranlukast is 225 mg) (Group 2) were cross-administered with 150 ml of water. The drug holiday was set at 1 week. Approximately 10 mL of blood was collected immediately before administration and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours after administration. The collected blood was placed in a heparin-treated vacuum tube and subjected to roller mixing for 5 minutes, and then centrifuged at 3000 rpm for 5 minutes. Plasma was collected into Eppendorf tubes and stored frozen at -70 ° C until analysis. The concentration of pranlukast in plasma was analyzed using LC / MS. The analysis results are shown in Table 3 and FIG.

  Even if the tablet of Example 12 manufactured from the wet granule according to the present invention is administered in a much lower volume (70 mg / tablet) than the total 225 mg of pranlukast of the existing onion capsule 2 capsules, It was confirmed that the drug had clinically equivalent efficacy.

[Test Example 4] Evaluation of pharmacokinetics in humans

  In accordance with the present invention, the pharmacokinetics in humans was evaluated using the produced tablets (Example 14) and onone capsules (taken as 2 capsules) as a commercial preparation.

  The test was performed in the same manner except for Test Example 3 and the test drug.

  The results are shown in Table 4 and FIG.

  Even if the tablet of Example 14 manufactured from the wet granule according to the present invention is administered at a dose (70 mg / tablet) that is far lower than the total 225 mg of pranlukast of the existing onion capsule 2 capsules, The values of AUCt and Cmax are about 38% and 33% higher than the commercial preparation, respectively. This is because tablets made from wet granules show improved bioavailability, and even when a dose of pranlukast is administered at a dose lower than 70 mg (about 50 mg), it can be compared with a commercial formulation and clinical It was confirmed that the drug had a similar level of efficacy.

[Test Example 5] Evaluation of pharmacokinetics in humans

  The pharmacokinetics in humans was evaluated using tablets (Example 17) produced according to the present invention and Onon capsules (2 capsules) as a commercial preparation.

  The test was conducted in the same manner except for Test Example 3 and the test drug.

  The results are shown in Table 5 below and FIG.

  The tablet of Example 17 manufactured from the wet granule according to the present invention has an AUCt even when administered at a dose (50 mg / tablet) far lower than the total 225 mg of pranlukast of the existing onion capsule 2 capsules. Since the / CmaxT / R ratio showed a result value at an equivalent level, it was confirmed that the drug efficacy was clinically equivalent to that of a commercially available preparation. In addition, since Tmax appears earlier than existing commercial preparations, it can be expected to develop an earlier drug effect in patients with bronchial asthma and allergic rhinitis, which are indications for pranlukast, and therapeutically existing commercial products are also available. It was confirmed that the formulation was improved.

  The present invention relates to a pharmaceutical composition containing granule mainly composed of pranlukast and produced by a wet granulation method, and the wet granulation method uses an alcohol having 1 to 6 carbon atoms as a binding solution solvent. The granules are characterized by comprising pranlukast, a surfactant, a binder and a diluent. As a result of the present invention, the dissolution rate of the drug is greatly improved compared to the existing onon capsules, and when the evaluation test of the pharmacokinetics in humans is conducted, the bioavailability of the drug is improved by about 4.5 times. In addition, even if the dosage volume of pranlukast is 50 mg per dose, it is a pharmaceutical that shows the same or better efficacy than existing commercial products.

  In addition, the production method of the present invention is characterized by adopting the wet granule method which is most widely used in the pharmaceutical industry, compared with the products with improved bioavailability of pranlukast and the related patented technology that have been previously marketed. However, this has the merit that there is substantially no difficulty in industrial application through the adoption of a simple manufacturing process and prevention of an increase in manufacturing cost.

Claims (9)

A pharmaceutical composition comprising granules produced by a wet granulation method,
The wet granulation method is characterized in that an alcohol having 1 to 6 carbon atoms is used as a binding liquid solvent, and the granule includes pranlukast, a surfactant, a binder and a diluent, and has a pharmaceutical composition The product comprises two or more disintegrants selected from the group consisting of crospovidone, sodium starch glycolate and croscarmellose sodium.   The composition according to claim 1, wherein the diluent is at least one selected from the group consisting of lactose and microcrystalline cellulose.   2. The composition according to claim 1, wherein the binder is at least one selected from the group consisting of polyvinyl pyrrolidone, polyvinyl pyrrolidone-vinyl acetate copolymer, and hydroxypropylmethylcellulose.   The surfactant is one or more selected from the group consisting of polyethylene glycol-15-hydroxystearate, polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene sorbitan fatty acid ester and sodium lauryl sulfate. The composition according to claim 1.   The composition according to claim 1, wherein the dose volume of pranlukast per administration is 70 mg or less.   The composition according to claim 1, wherein the diluent is contained in an amount of 20 to 60% based on the weight of the entire composition.   The composition according to claim 1, wherein the binder is contained in an amount of 2 to 10% based on the weight of the entire composition.   The composition according to claim 1, wherein the surfactant is contained in an amount of 5 to 20% based on the weight of the entire composition.   9. A preparation comprising the pharmaceutical composition according to claim 1, wherein the preparation is a granule, tablet, orally disintegrating agent, chewable tablet, suspension tablet, capsule, fine granule or dry syrup. The formulation characterized by being.

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